1. Field of Invention
The present invention relates to a process for the synthesis of 3-phenoxy-1-azetidinecarboxamides, particularly 3-(3-trifluoromethylphenoxy)-1-azetidine-carboxamide, in which an appropriately substituted 3-phenoxyazetidine is fused with urea. The compounds prepared by the process of this invention are useful as anticonvulsants.
2. Information Disclosure Statement
Anticonvulsant 3-phenoxy-1-azetidinecarboxamides as shown in Formula I: ##STR2## where n is 1-3, R is H, and X is selected from hydrogen, fluorine, loweralkyl, loweralkoxy, trifluoromethyl, acetyl or aminocarbonyl are disclosed in U.S. Pat. No. 4,571,393. U.S. Pat. No. 4,956,359 further discloses 3-phenoxy-1-azetidinecarboxamides of Formula I in which X, among other things, is chlorine, bromine or iodine and R is H or methyl. The methods of preparation of Formula I carboxamides as disclosed hereinabove involve reaction of a Formula II intermediate where n, X and R ##STR3## are as defined under Formula I below with either nitrourea or phosgene/ammonium hydroxide. The reaction with nitrourea involves heating a Formula II compound with nitrourea in an appropriate organic solvent such as ethanol. Nitrourea is relatively expensive, somewhat unstable, and potentially explosive and thus is not the reagent of choice for a large scale reaction. The synthetic procedure involving phosgene requires formation of a 3-phenoxyazetidine-1-carbonyl chloride from a Formula II intermediate followed by reaction of the carbamoyl chloride with ammonium hydroxide. Both phosgene and ammonium hydroxide are toxic and formation of the carbamoyl chloride requires the use of an anhydrous aprotic solvent. The Formula II intermediate is prepared from the N-protected intermediate having the structure shown as Formula III: ##STR4## where n, X and R are as defined under Formula I below and Y is methyl or phenyl by catalytic hydrogenolysis in the presence of an appropriate hydrogenation catalyst to remove the --CHYC.sub.6 H.sub.5 group. An alternative procedure for preparing the 3-phenoxyazetidine-1-carbonyl chloride is to react a Formula III compound with phosgene, which N-dealkylates the Formula III compound, giving the corresponding carbamoyl chloride and the chlorinated by-product, ClCHYC.sub.6 H.sub.5 which is a lachrymator and skin and lung irritant. The above synthetic procedures are given in the U.S. patent cited hereinabove and in U.S. Pat. Nos. 4,954,189 and 4,379,151.
Reactions of urea with primary alkylamines to obtain monosubstituted ureas which may be further reacted to give symmetrical dialkylureas, alkylbiurets and dialkylbiurets appear in the literature. T. L. Davis and H. W. Underwood, Jr., J. Amer. Chem. Soc. 44, 2596-2597 (1922) report that no reaction occurs between urea and diphenylamine or N-ethylaniline and that with dibutyl and diamylamines or their hydrochlorides, the formation of a by-product, ammonium chloride, indicated that reaction had taken place, although the products were exceedingly difficult to separate. T. L. Davis and K. C. Blanchard, J. Amer. Chem. Soc. 45, 1817 (1923), report that when an aqueous solution of urea and N-methylaniline hydrochloride or N-ethylaniline hydrochloride was refluxed, the corresponding unsymmetrical ureas were produced in poor yields. J. C. Erikson, J. Amer. Chem. Soc. 76, 3977-8 (1954) reported the synthesis of 1,1-dioctadecylurea from dioctadecylamine and urea heated together at 160.degree.-165.degree. C. for 5 hours.